Propanedinitrile, 2-amino-, 4-methylbenzenesulfonate (1:1)

To a suspension of aminomalononitrile 7-toluenesulfonate (1 g, 4.0 mmol, 1 equiv) in THF (30 mL) at 25 C was added NEt3 (0.65 mL, 4.8 mmol, 1.2 equiv) in one portion. The mixture was stirred for 30 min to afford a homogeneous solution. To this solution was added triethyl orthoformate (0.80 mL, 4.8 mmol, 1.2 equiv) and the solution was heated at reflux for 3 h. TLC indicated the presence of starting material and additional triethyl orthoformate (0.4 mL, 2.4 mmol, 0.6 equiv) was added. The solution was heated at reflux for another 2 h then cooled to 25 C. NEt3 (0.65 mL, 4.8 mmol, 1.2 equiv) and isobutylamine (350 mg, 4.8 mmol, 1.2 equiv) were added sequentially and the reaction was stirred at 25 C for 15 h. The reaction was concentrated in vacuo and the crude residue was redissolved in CH2C12 (100 mL) and washed with saturated Na2C03 solution (25 mL). The aqueous layer was extracted with CH2C12 (3 x 20 mL). The combined organic fractions were washed with saturated aqueous NaCl, dried (MgS04), and concentrated in vacuo. Purification by flash column chromatography on silica gel (CH2Cl2-l/9 MeOH/CFL ., gradient) afforded the title compound (426 mg, 65%) as a light yellow solid: 1H NMR (CDCI3, 600 Hz) delta 0.96 (d, J= 6.6 Hz, 6H), 2.01-2.07 (m, 1H), 3.57 (d, J= 7.8 Hz, 2H), 3.94 (br s, 2H), 7.05 (s, 1H); 13C NMR (CDC13, 150 Hz) delta 19.8, 28.9, 51.6, 115.7, 116.5, 133.5, 144.8; MS (ESI+): calcd C8H13N4 [M+H]+ 165.1, found 165.1.Step (a) 5-Amino-1-(2-methylpropyl)imidazole4-carbonitrile (1). Anhydrous ammonia was passed, at room temperature, through a stirred suspension of aminonitrile tosylate (10 g, 39 mmol) in 200 mL CH3CN. After 45 min, ammonia was stopped and the solution was cooled at 15C. The solid was filtered off and washed once with 10 mL CH3CN, The filtrate was combined with the washing and concentrated to half of its volume. To this solution, triethyl orthoformate (6.6 mL, 39.5 mmol) was added and the solution was refluxed 30 min. After cooling to r.t, 2-methylpropylamine (iso-butylamine) (3.95 mL, 39.5 mmol) was added and the mixture was stirred overnight at r.t. The solution was evaporated to dryness in vacuo and the residue was partitioned between CH2Cl2 and 2N Na2CO3. The organic layer was evaporated and the residue was triturated in 20 mL AcOEt. The brown crystals that separated were separated and could be used for the next step. Yield: 50-60 %. An analytical sample was prepared by crystallisation from AcOEt.; Mp: 193-195C. 1H-NMR (400 MHz, CDCl3) delta 0.91 (d, 6H, 2CH3); 1.98 (non, 1H, CH); 3.50 (d, 2H, CH2); 3.83 (br s, 2H, NH2); 6.97 (s, 1H, imidazole). 13C-NMR (100 MHz, CDCl3) 20.24; 29.38; 51.96; 116.11; 113.89.Step c - mixture of 2-(1-(4-methoxybenzyl)-1H-indazol-4-yl)-5-aminooxazole-4- carbonitrile and 2-(2-(4-methoxybenzyl)-2H-indazol-4-yl)-5-aminooxazole-4-carbonitrile; A mixture of 1-(4-methoxybenzyl)-1 H-indazole-4-carboxylic acid and 2-(4- methoxybenzyl)-2H-indazole-4-carboxylic acid (1.07g, 3.79mmol) was taken up in a mixture of DCM (10ml) and DMF (100mul) and then oxalyl chloride (0.38ml, 4.55mmol) was added dropwise. After stirring at room temperature for 2 hours the solvent was removed in vacuo and the residue dissolved in NMP (5ml). To this solution was added aminomalononitrile tosylate (1.15g, 4.55mmol) and the reaction heated to 12O0C under microwave irradiation for a period of 5 minutes. The reaction mixture was then diluted with DCM and washed with water. The resulting white precipitate was filtered off and dried in vacuo to give 1.1g (3.20mmol, 84%) of a white powdery solid containing a mixture of the two regioisomers. LCMS (3) 2.15 and 2.25 min; m/z (ES-) 344.Example F-1; 2-(2, 6-difluorophenyl)-5-phenyloxazole-4-carboxamide; Step a - 5-amino-2-(2, 6-difluorophenyl)oxazole-4-carbonitrile; To a solution of aminomalononitrile p-toluenesulfonate (0.05Og, 0.2mmol) in NMP (0.5ml_) was added 2, 6-difluorobenzoyl chloride (27ul, 0.21 mmol) and the resulting solution heated in the microwave at 12O0C for 5 minutes. The solution was diluted with EtOAc and water. The organic phase was washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to afford 5-amino-2-(2, 6- difluorophenyl)oxazole-4-carbonitrile (0.03Og, 0.14mmol, 69%) as an off-white solid. 1H NMR (DMSO) delta 7.30 (2H, t), 7.61 (1 H, m), 8.14 (2H, br. s). LCMS (1) Rt: 1.59 min; m/z (ES+) 222.To a solution of glycol (15 ml, 30% w/v in H2O) and acetone oxime (5.0 g) in H2O (20 mL) was added aminomalononitrile />-toluenesulfonate (16.41 g) and the resulting mixture was stirred overnight at room temperature. The title compound started to precipitate after 10 minutes of complete dissolution of the aminomalonitrile p-toluenesulfonate had occurred, and was collected by filtration the next day as the^»-toluenesulfonate salt.LCMS: [M+Hf 169.1H nuMR (300 MHz, DMSO-d6) delta 8.72 (d, 1 H) 8.49 (d, 2 H), 8.00 (br.s, 1 H) 7.86 (d, 2 H), 7.55(s, 1 H) 2.56 (s, 3 H).General procedure: In a 35 mL microwave tube equipped with a magnetic stirrer, aminomalononitrile 4-toluenesulfonate (127 mg, 0.50 mmol), N-methylpyrrolidone (5 mL) and thiophene-2-carbonyl chloride (0.09 mL, 0.60 mmol) were added. The vessel was then sealed using a rubber microwave septum and then placed into the microwave cavity. The reaction mixture was irradiated with 200 W of power and heated to 120C (dynamic profile with cooling). When at 120C it was held by moderation of the power. The vessel was then cooled to rt. The reaction mixture was extracted with ethyl acetate (20 mL) and was initially washed with deionised water (2x15 mL), followed by sat. Na2CO3 (2x15 mL). The organic layer was then dried with MgSO4, filtered then evaporated. Using a combiflash R75 the crude reaction mixture was purified using 1:4 ethyl acetate/ methylene chloride as the elutant to give 4a (91 mg, 94% yield) as a white solid.General procedure: These compounds were synthesized according to the previouslydescribed procedure [38]. To a stirred solution of 1.7 g of aminomalononitriletosylate 16 (4.6 mmol) in 1-methyl-2-pyrrolidinone(12 mL, 117.0 mmol) the suitable benzoyl chloride 15a-c(5.1 mmol) was added. The reaction mixture was stirred at roomtemperature for 12 h and then, diluted with 100mL of a 1:1 solutionof ethyl acetate: ethyl ether, washed with water (2 100 mL), and a 10% saturated solution of sodium hydrogen carbonate(2 100 mL). The organic layerwas dried over sodium sulphate andthe solvent removed under reduced pressure.General procedure: Aminomalononitrile tosylate(9.2 mmol) was dissolved in anhydrous 1-methyl-2-pyrrolidinone (30 mL). Aryl isothiocyanate(9.2 mmol) was added dropwise while stirring. The mixture was stirred for ca 20 h at 22-24Cunder stirring. It was then diluted with 1:1 ethyl acetate / diethyl ether (150 mL), transferred to aseparatory funnel and washed with water (2 × 100 mL). The organic layer was separated, driedwith anhydrous sodium sulfate and filtered, and the solvent was removed in vacuo. The residuewas chromatographed on silica gel with EtOAc / dichloromethane (1:9 to 3:7) to afford thethiazoles.General procedure: Aminomalononitrile tosylate(9.2 mmol) was dissolved in anhydrous 1-methyl-2-pyrrolidinone (30 mL). Aryl isothiocyanate(9.2 mmol) was added dropwise while stirring. The mixture was stirred for ca 20 h at 22-24Cunder stirring. It was then diluted with 1:1 ethyl acetate / diethyl ether (150 mL), transferred to aseparatory funnel and washed with water (2 × 100 mL). The organic layer was separated, driedwith anhydrous sodium sulfate and filtered, and the solvent was removed in vacuo. The residuewas chromatographed on silica gel with EtOAc / dichloromethane (1:9 to 3:7) to afford thethiazoles.5-Amino-2-(phenylamino)-1, 3-thiazole-4-carbonitrile (2a). Red-brownish solid, m.p. 164-166C (164-1657) IR: 3691 (NH), 3355 and 3289 (NH2), 2198 (CN), 1597 (NH2), 1575 (NH), 1345 (NH2), 743 and 684 (monosubstituted benzene) cm-1. 1H NMR (DMSO-d6): delta 6.1 (s, 2H, NH2), 6.8 (t, 1H, CH, J = 8.5 Hz), 7.1 (t, 2H, 2 × CH, J = 8.5 Hz), 7.4 (d, 2H, 2 × CH, J = 8.5Hz), 9.3 (s, 1H, NH). 13C NMR (DMSO-d6): delta 95.6, 116.4, 116.6, 120.8, 128.9, 141.0, 147.8, 154.4.

Molecular Weight:253.28
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:1
Exact Mass:253.05211239
Monoisotopic Mass:253.05211239
Topological Polar Surface Area:136
Heavy Atom Count:17
Complexity:310
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes